Publications by authors named "Naoto Kubota"

148 Publications

LPL/AQP7/GPD2 promotes glycerol metabolism under hypoxia and prevents cardiac dysfunction during ischemia.

FASEB J 2021 Dec;35(12):e22048

Department of Cardiology, Nagoya University School of Medicine, Nagoya, Japan.

In the heart, fatty acid is a major energy substrate to fuel contraction under aerobic conditions. Ischemia downregulates fatty acid metabolism to adapt to the limited oxygen supply, making glucose the preferred substrate. However, the mechanism underlying the myocardial metabolic shift during ischemia remains unknown. Here, we show that lipoprotein lipase (LPL) expression in cardiomyocytes, a principal enzyme that converts triglycerides to free fatty acids and glycerol, increases during myocardial infarction (MI). Cardiomyocyte-specific LPL deficiency enhanced cardiac dysfunction and apoptosis following MI. Deficiency of aquaporin 7 (AQP7), a glycerol channel in cardiomyocytes, increased the myocardial infarct size and apoptosis in response to ischemia. Ischemic conditions activated glycerol-3-phosphate dehydrogenase 2 (GPD2), which converts glycerol-3-phosphate into dihydroxyacetone phosphate to facilitate adenosine triphosphate (ATP) synthesis from glycerol. Conversely, GPD2 deficiency exacerbated cardiac dysfunction after acute MI. Moreover, cardiomyocyte-specific LPL deficiency suppressed the effectiveness of peroxisome proliferator-activated receptor alpha (PPARα) agonist treatment for MI-induced cardiac dysfunction. These results suggest that LPL/AQP7/GPD2-mediated glycerol metabolism plays an important role in preventing myocardial ischemia-related damage.
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http://dx.doi.org/10.1096/fj.202100882RDOI Listing
December 2021

Differential involvement of insulin receptor substrate (IRS)-1 and IRS-2 in brain insulin signaling is associated with the effects on amyloid pathology in a mouse model of Alzheimer's disease.

Neurobiol Dis 2021 11 16;159:105510. Epub 2021 Sep 16.

Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address:

Insulin signaling has been implicated in the metabolism as well as aging and longevity. Type 2 diabetes mellitus and its core pathology, insulin resistance, has also been implicated in the development of Alzheimer's disease (AD) and amyloid-β deposition in humans. By contrast, genetic ablation of the insulin/IGF-1 signaling (IIS) pathway components, e.g. insulin receptor substrate (IRS)-2, has been documented to suppress amyloid-β accumulation in the brains of transgenic mice overexpressing AD mutant β-amyloid precursor protein (APP). Therefore, the brain IIS may be a key modifiable molecular target in the pathophysiology of AD. IRS-1 and IRS-2 are critical nodes in IIS as substrates for insulin receptor and IGF-1 receptor, although the functional differences between IRS-1 and IRS-2 in the adult brain are yet to be explored. To examine their relative contribution to the brain IIS activity and AD pathomechanism, we generated APP transgenic mice lacking either IRS-1 or IRS-2. IRS-1 deficiency had little effects on the brain IIS pathway associated with compensatory activation of IRS-2, whereas IRS-2 deficiency was not fully compensated by activation of IRS-1, and the downstream activation of Akt also was significantly compromised. Pathological analyses of the cortical tissues showed that the biochemical levels of soluble and insoluble amyloid-β, the amyloid-β histopathology, and tau phosphorylation were not affected by the absence of IRS-1, in contrast to the marked alteration in IRS-2 deleted mice. These results suggest the predominance of IRS-2 in the brain IIS, and support the hypothesis that reduced IIS exerts anti-amyloid effects in the brain.
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http://dx.doi.org/10.1016/j.nbd.2021.105510DOI Listing
November 2021

A xanthene derivative, DS20060511, attenuates glucose intolerance by inducing skeletal muscle-specific GLUT4 translocation in mice.

Commun Biol 2021 08 20;4(1):994. Epub 2021 Aug 20.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Reduced glucose uptake into the skeletal muscle is an important pathophysiological abnormality in type 2 diabetes, and is caused by impaired translocation of glucose transporter 4 (GLUT4) to the skeletal muscle cell surface. Here, we show a xanthene derivative, DS20060511, induces GLUT4 translocation to the skeletal muscle cell surface, thereby stimulating glucose uptake into the tissue. DS20060511 induced GLUT4 translocation and stimulated glucose uptake into differentiated L6-myotubes and into the skeletal muscles in mice. These effects were completely abolished in GLUT4 knockout mice. Induction of GLUT4 translocation by DS20060511 was independent of the insulin signaling pathways including IRS1-Akt-AS160 phosphorylation and IRS1-Rac1-actin polymerization, eNOS pathway, and AMPK pathway. Acute and chronic DS20060511 treatment attenuated the glucose intolerance in obese diabetic mice. Taken together, DS20060511 acts as a skeletal muscle-specific GLUT4 translocation enhancer to facilitate glucose uptake. Further studies of DS20060511 may pave the way for the development of novel antidiabetic medicines.
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http://dx.doi.org/10.1038/s42003-021-02491-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379256PMC
August 2021

A Case of Chronic Intestinal Pseudo-obstruction with Mitochondrial Diseases.

Intern Med 2021 Aug 13. Epub 2021 Aug 13.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Japan.

Chronic intestinal pseudo-obstruction (CIPO) is a rare disorder of intestinal dysmotility characterized by chronic symptoms, including vomiting and abdominal pain, associated with bowel obstruction without any mechanical obstructive causes. We herein report a case of mitochondrial diseases with recurrent duodenal obstruction that was initially diagnosed as superior mesenteric artery syndrome (SMAS) for a few years but was later diagnosed as CIPO. Since CIPO is known to be associated with mitochondrial diseases, it should be considered in the differential diagnosis of patients with mitochondrial diseases presenting with recurrent intestinal obstruction.
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http://dx.doi.org/10.2169/internalmedicine.7714-21DOI Listing
August 2021

Protein intake after the initiation of chemotherapy is an independent prognostic factor for overall survival in patients with unresectable pancreatic cancer: A prospective cohort study.

Clin Nutr 2021 07 17;40(7):4792-4798. Epub 2021 Jun 17.

Clinical Nutrition Center, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan; Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. Electronic address:

Background & Aims: This study was conducted to investigate the nutritional status and longitudinal dietary intake during the course of chemotherapy, and their relationships with the survival in patients with unresectable pancreatic cancer.

Methods: A prospective cohort study was conducted in 38 patients with unresectable pancreatic cancer receiving chemotherapy between January 2018 and November 2019. Subjective global assessment was used to assess the nutritional status, and the dietary intake was assessed monthly, for up to 12 months, using a brief self-administered diet history questionnaire. The primary outcome was overall survival, and the secondary outcome was progression-free survival. Cox regression analysis was performed to identify independent prognostic factors.

Results: Moderate or severe malnutrition was found in 34.2% of the participants. Daily protein intake was significantly higher in the survivor group than in the deceased group at one month after the initiation of chemotherapy (1.4 ± 0.7 g/kg/day vs. 0.9 ± 0.5 g/kg/day, p = 0.019), while the baseline nutritional intakes were similar between the two groups. Univariate analysis identified weight loss >3.5%, energy intake <25 kcal/kg/day, protein intake <1.1 g/kg/day, and malnutrition as possible poor prognostic factors. Multivariate analysis identified protein intake <1.1 g/kg/day (hazard ratio [HR]: 9.03, 95%CI: 1.45-56.32, p = 0.018) as an independent poor prognostic factor.

Conclusions: Insufficient protein intake was identified as an independent poor prognostic factor in patients with unresectable pancreatic cancer receiving chemotherapy. Improving the dietary protein intake could be a useful therapeutic approach in patients with advanced pancreatic cancer receiving chemotherapy.
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http://dx.doi.org/10.1016/j.clnu.2021.06.011DOI Listing
July 2021

Gamma-synuclein is a novel prognostic marker that promotes tumor cell migration in biliary tract carcinoma.

Cancer Med 2021 08 9;10(16):5599-5613. Epub 2021 Jul 9.

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

Gamma-synuclein (SNCG) promotes invasive behavior and is reportedly a prognostic factor in a range of cancers. However, its role in biliary tract carcinoma (BTC) remains unknown. Consequently, we investigated the clinicopathological significance and function of SNCG in BTC. Using resected BTC specimens from 147 patients with adenocarcinoma (extrahepatic cholangiocarcinoma [ECC, n = 96]; intrahepatic cholangiocarcinoma [ICC, n = 51]), we immunohistochemically evaluated SNCG expression and investigated its correlation with clinicopathological factors and outcomes. Furthermore, cell lines with high SNCG expression were selected from 16 BTC cell lines and these underwent cell proliferation and migration assays by siRNAs. In the results, SNCG expression was present in 22 of 96 (22.9%) ECC patients and in 10 of 51 (19.6%) ICC patients. SNCG expression was significantly correlated with poorly differentiated tumor in both ECC and ICC (p = 0.01 and 0.03, respectively) and with perineural invasion and lymph node metastases in ECC (p = 0.04 and 0.003, respectively). Multivariate analyses revealed that SNCG expression was an independent poor prognostic factor in both OS and RFS in both ECC and ICC. In vitro analyses showed high SNCG expression in three BTC cell lines (NCC-BD1, NCC-BD3, and NCC-CC6-1). Functional analysis revealed that SNCG silencing could suppress cell migration in NCC-BD1 and NCC-CC6-1 and downregulate cell proliferation in NCC-CC6-1 significantly. In conclusion, SNCG may promote tumor cell activity and is potentially a novel prognostic marker in BTC.
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http://dx.doi.org/10.1002/cam4.4121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366101PMC
August 2021

Stool pattern is associated with not only the prevalence of tumorigenic bacteria isolated from fecal matter but also plasma and fecal fatty acids in healthy Japanese adults.

BMC Microbiol 2021 06 28;21(1):196. Epub 2021 Jun 28.

Department of Physical Activity Research, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Tokyo, 162-8636, Japan.

Background: Colibactin-producing Escherichia coli containing polyketide synthase (pks E. coli) has been shown to be involved in colorectal cancer (CRC) development through gut microbiota analysis in animal models. Stool status has been associated with potentially adverse gut microbiome profiles from fecal analysis in adults. We examined the association between stool patterns and the prevalence of pks E. coli isolated from microbiota in fecal samples of 224 healthy Japanese individuals.

Results: Stool patterns were determined through factorial analysis using a previously validated questionnaire that included stool frequency, volume, color, shape, and odor. Factor scores were classified into tertiles. The prevalence of pks E. coli was determined by using specific primers for pks E. coli in fecal samples. Plasma and fecal fatty acids were measured via gas chromatography-mass spectrometry. The prevalence of pks E. coli was 26.8%. Three stool patterns identified by factorial analysis accounted for 70.1% of all patterns seen (factor 1: lower frequency, darker color, and harder shape; factor 2: higher volume and softer shape; and factor 3: darker color and stronger odor). Multivariable-adjusted odds ratios (95% confidence intervals) of the prevalence of pks E. coli for the highest versus the lowest third of the factor 1 score was 3.16 (1.38 to 7.24; P for trend = 0.006). This stool pattern exhibited a significant positive correlation with fecal isobutyrate, isovalerate, valerate, and hexanoate but showed a significant negative correlation with plasma eicosenoic acid and α-linoleic acid, as well as fecal propionate and succinate. No other stool patterns were significant.

Conclusions: These results suggest that stool patterns may be useful in the evaluation of the presence of tumorigenic bacteria and fecal fatty acids through self-monitoring of stool status without the requirement for specialist technology or skill. Furthermore, it may provide valuable insight about effective strategies for the early discovery of CRC.
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http://dx.doi.org/10.1186/s12866-021-02255-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240356PMC
June 2021

Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus.

Diabetes 2021 08 12;70(8):1640-1653. Epub 2021 May 12.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Insulin receptor substrate-1 (Irs1) is one of the major substrates for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor tyrosine kinases. Systemic Irs1-deficient mice show growth retardation, with resistance to insulin and IGF-1, although the underlying mechanisms remain poorly understood. For this study, we generated mice with brain-specific deletion of Irs1 (NIrs1KO mice). The NIrs1KO mice exhibited lower body weights, shorter bodies and bone lengths, and decreased bone density. Moreover, the NIrs1KO mice exhibited increased insulin sensitivity and glucose utilization in the skeletal muscle. Although the ability of the pituitary to secrete growth hormone (GH) remained intact, the amount of hypothalamic growth hormone-releasing hormone (GHRH) was significantly decreased and, accordingly, the pituitary GH mRNA expression levels were impaired in these mice. Plasma GH and IGF-1 levels were also lower in the NIrs1KO mice. The expression levels of GHRH protein in the median eminence, where Irs1 antibody staining is observed, were markedly decreased in the NIrs1KO mice. In vitro, neurite elongation after IGF-1 stimulation was significantly impaired by Irs1 downregulation in the cultured N-38 hypothalamic neurons. In conclusion, brain Irs1 plays important roles in the regulation of neurite outgrowth of GHRH neurons, somatic growth, and glucose homeostasis.
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http://dx.doi.org/10.2337/db20-0482DOI Listing
August 2021

Midlobular zone 2 hepatocytes: A gatekeeper of liver homeostasis.

Cell Metab 2021 05;33(5):855-856

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Toranomon Hospital, Tokyo, Japan. Electronic address:

The liver consists of different zones that vary in function depending on their lobular localization. It remained unclear which zone serves as a source of repopulating/regenerating hepatocytes; however, experiments by Wei et al. (2021) in 11 CreER knockin murine strains revealed a vital role for zone 2 hepatocytes in liver homeostasis.
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http://dx.doi.org/10.1016/j.cmet.2021.04.005DOI Listing
May 2021

Role of Insulin Resistance in MAFLD.

Int J Mol Sci 2021 Apr 16;22(8). Epub 2021 Apr 16.

Toranomon Hospital, Tokyo 105-8470, Japan.

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.
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http://dx.doi.org/10.3390/ijms22084156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072900PMC
April 2021

Deep Ultraviolet Light-Emitting Diode Light Therapy for .

Microorganisms 2021 Feb 19;9(2). Epub 2021 Feb 19.

Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Ube 7558505, Japan.

Background: , which is associated with periodontitis and gingivitis, has been detected in colorectal cancer (CRC).

Methods: We evaluated the bactericidal effect of deep ultraviolet (DUV) light-emitting diode (LED) light therapy on both qualitatively and quantitatively. Two DUV-LEDs with peak wavelengths of 265 and 280-nm were used. DNA damage to was evaluated by the production of cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP).

Results: DUV-LEDs showed a bactericidal effect on . No colony growth was observed after 3 min of either 265 nm or 280 nm DUV-LED irradiation. The survival rates of under 265 nm DUV-LED light irradiation dropped to 0.0014% for 10 s and to 0% for 20 s irradiation. Similarly, the survival rate of under 280 nm DUV-LED light irradiation dropped to 0.00044% for 10 s and 0% for 20 s irradiation. The irradiance at the distance of 35 mm from the DUV-LED was 0.265 mW/cm for the 265 nm LED and 0.415 mW/cm for the 280 nm LED. Thus, the radiant energy for lethality was 5.3 mJ/cm for the 265 nm LED and 8.3 mJ/cm for the 280 nm LED. Amounts of CPD and 6-4PP in irradiated with 265 nm DUV-LED light were 6.548 ng/µg and 1.333 ng/µg, respectively.

Conclusions: DUV-LED light exerted a bactericidal effect on by causing the formation of pyrimidine dimers indicative of DNA damage. Thus, DUV-LED light therapy may have the potential to prevent CRC.
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http://dx.doi.org/10.3390/microorganisms9020430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922187PMC
February 2021

Transcriptome-Guided Design of Physiological Multilineage Liver Organoids.

Trends Genet 2021 05 1;37(5):403-404. Epub 2021 Feb 1.

Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address:

Despite several technical challenges, human induced pluripotent stem cell (hiPSC)-derived organoids enable biologically and clinically relevant functional study of physiology and disease. In a recent Cell Systems article, Velazquez et al. report a novel strategy to identify regulators of multilineage organoid maturation by reverse-engineering from the global transcriptome of human tissues.
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http://dx.doi.org/10.1016/j.tig.2021.01.007DOI Listing
May 2021

Sex-related differences in the effects of nutritional status and body composition on functional disability in the elderly.

PLoS One 2021 2;16(2):e0246276. Epub 2021 Feb 2.

Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: The aim of our study was to evaluate the influence of changes of nutritional status and body composition on the results of comprehensive geriatric assessment (CGA) in inpatients of a geriatric ward. Sex differences in these relationships were also investigated.

Methods: A total of 212 elderly patients (>65 years old) admitted to the geriatric ward at the University of Tokyo hospital between 2012 and 2019 were enrolled in this study. CGA (ADL, IADL, MMSE, GDS, Vitality Index) was performed, along with assessment of body compositions (appendicular muscle mass, abdominal muscle mass, body fat mass) and blood malnutrition biomarkers (serum albumin, pre-albumin, 25-hydroxy vitamin D, zinc, hemoglobin concentrations).

Results: Multiple linear regression analysis showed that upper, lower limbs and abdominal muscle masses were significantly associated with the score on ADL in men. On the other hand, abdominal muscle mass was negatively associated with the scores on GDS. Body fat mass was also negatively associated with the score on IADL. In contrast, in women, multiple linear regression analysis failed to show any significant associations between body composition parameters and scores on any domains of CGA. Unlike in men, however, blood malnutrition biomarkers were significantly associated with ADL, IADL, MMSE, and Vitality Index in women.

Conclusions: Our study findings revealed that the association of the nutritional status and body composition with the functional status in the elderly differs by sex. These results suggest that intensification of exercise in men and improvement of the nutritional status in women are particularly useful to maintain the functional status.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246276PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853464PMC
July 2021

Acquired amegakaryocytic thrombocytopenia after durvalumab administration.

J Clin Exp Hematop 2021 Mar 8;61(1):53-57. Epub 2021 Jan 8.

Departments of Internal Medicine,Nippon Koukan Hospital, Kawasaki, Kanagawa, Japan.

Immune checkpoint inhibitors (ICIs), despite their ability to potentiate antitumor T-cell responses, may cause various immune-related adverse events. Most cases of thrombocytopenia induced by ICIs have revealed a pathophysiologic mechanism of immune thrombocytopenia with increased platelet destruction and preserved megakaryocytes. Acquired amegakaryocytic thrombocytopenic purpura (AATP) is an unusual disorder characterized by thrombocytopenia with markedly diminished bone marrow megakaryocytes in the presence of otherwise normal hematopoiesis. AATP caused by ICIs has not been reported on. Herein, we present the case of a 79-year-old man diagnosed with squamous cell carcinoma of the lung who developed AATP after two courses of durvalumab, a drug targeting programmed death-ligand 1. Two weeks after the second cycle, his platelet count decreased to 2.1 × 10/μL. After the patient underwent platelet transfusion, his platelet count increased to 8.1 × 10/μL the next day but subsequently decreased repeatedly even after the ICI was discontinued. Six weeks after the second cycle, he developed interstitial pneumonia and was administered prednisolone (50 mg/day). However, thrombocytopenia did not improve. Bone marrow biopsy showed scarce megakaryocytes (< 1 megakaryocyte/10 high-power fields) with preservation of myeloid and erythroid series. Myelodysplasia, myelofibrosis, or metastatic lesions were not observed. Cytogenetic analysis showed a normal male karyotype of 46XY. Hence, the patient received eltrombopag, a thrombopoietin receptor agonist, and his platelet count subsequently improved. After recovery, bone marrow aspiration revealed a normal number of megakaryocytes. AATP is rarely the type of thrombocytopenia induced by ICIs and may be successfully treated with thrombopoietin receptor agonists.
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http://dx.doi.org/10.3960/jslrt.20047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053569PMC
March 2021

Hepatocellular carcinoma development in diabetic patients: a nationwide survey in Japan.

J Gastroenterol 2021 03 11;56(3):261-273. Epub 2021 Jan 11.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Although type 2 diabetes mellitus (T2DM) is a known risk factor for hepatocellular carcinoma (HCC) development, the annual incidence in diabetes patients is far below the threshold of efficient surveillance. This study aimed to elucidate the risk factors for HCC in diabetic patients and to determine the best criteria to identify surveillance candidates.

Methods: The study included 239 patients with T2DM who were diagnosed with non-viral HCC between 2010 and 2015, with ≥ 5 years of follow-up at diabetes clinics of 81 teaching hospitals in Japan before HCC diagnosis, and 3277 non-HCC T2DM patients from a prospective cohort study, as controls. Clinical data at the time of and 5 years before HCC diagnosis were collected.

Results: The mean patient age at HCC diagnosis was approximately 73 years, and 80% of the patients were male. The proportion of patients with insulin use increased, whereas the body mass index (BMI), proportion of patients with fatty liver, fasting glucose levels, and hemoglobin A1c (HbA1c) levels decreased significantly in 5 years. In the cohort study, 18 patients developed HCC during the mean follow-up period of 4.7 years with an annual incidence of 0.11%. Multivariate logistic regression analyses showed that the FIB-4 index was an outstanding predictor of HCC development along with male sex, presence of hypertension, lower HbA1c and albumin levels, and higher BMI and gamma-glutamyl transpeptidase levels. Receiver-operating characteristic analyses showed that a FIB-4 cut-off value of 3.61 could help identify high-risk patients, with a corresponding annual HCC incidence rate of 1.1%.

Conclusion: A simple calculation of the FIB-4 index in diabetes clinics can be the first step toward surveillance of HCC with a non-viral etiology.
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http://dx.doi.org/10.1007/s00535-020-01754-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932951PMC
March 2021

Clinical and Molecular Prediction of Hepatocellular Carcinoma Risk.

J Clin Med 2020 Nov 26;9(12). Epub 2020 Nov 26.

Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.

Prediction of hepatocellular carcinoma (HCC) risk becomes increasingly important with recently emerging HCC-predisposing conditions, namely non-alcoholic fatty liver disease and cured hepatitis C virus infection. These etiologies are accompanied with a relatively low HCC incidence rate (~1% per year or less), while affecting a large patient population. Hepatitis B virus infection remains a major HCC risk factor, but a majority of the patients are now on antiviral therapy, which substantially lowers, but does not eliminate, HCC risk. Thus, it is critically important to identify a small subset of patients who have elevated likelihood of developing HCC, to optimize the allocation of limited HCC screening resources to those who need it most and enable cost-effective early HCC diagnosis to prolong patient survival. To date, numerous clinical-variable-based HCC risk scores have been developed for specific clinical contexts defined by liver disease etiology, severity, and other factors. In parallel, various molecular features have been reported as potential HCC risk biomarkers, utilizing both tissue and body-fluid specimens. Deep-learning-based risk modeling is an emerging strategy. Although none of them has been widely incorporated in clinical care of liver disease patients yet, some have been undergoing the process of validation and clinical development. In this review, these risk scores and biomarker candidates are overviewed, and strategic issues in their validation and clinical translation are discussed.
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http://dx.doi.org/10.3390/jcm9123843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761278PMC
November 2020

Diets with high carbohydrate contents were associated with refeeding hypophosphatemia: A retrospective study in Japanese inpatients with anorexia nervosa.

Int J Eat Disord 2021 01 24;54(1):88-94. Epub 2020 Nov 24.

Department of Stress Sciences and Psychosomatic Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objective: Refeeding hypophosphatemia (RH) is a potentially fatal complication in patients with anorexia nervosa (AN), and its dietary preventive strategy is not well established. We aimed to examine the association between carbohydrate content in the diet and the occurrence of RH in inpatients with AN via retrospective medical chart review.

Method: We performed a chart review to collect data of patients with AN hospitalized at the Department of Psychosomatic Medicine of the University of Tokyo Hospital between April 1, 2012, and February 29, 2020. Receiver operating characteristic (ROC) analysis was performed to determine the cutoff point of the percentage of carbohydrate content in the diet for the occurrence of RH. Multivariate logistic regression analysis was performed with occurrence of RH as the dependent variable and the carbohydrate content of more than the identified cutoff point as the independent variable adjusting for the risk factors for RH.

Results: The percentage of carbohydrate content that is higher than the cutoff point obtained from the ROC analysis (58.4%) was significantly associated with the occurrence of RH, even after adjusting for variables associated with RH in univariate logistic regression analysis (age and body mass index) as well as the average daily calorie intake (odds ratio, 5.37; 95% confidence interval, 1.60-18.1; p = .0066).

Discussion: We identified that diets with higher carbohydrate contents were associated with RH in inpatients with AN, even after adjusting for known risk factors. Our findings may promote the development of dietary preventive strategies against RH in inpatients with AN.
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http://dx.doi.org/10.1002/eat.23416DOI Listing
January 2021

Using mHealth to Provide Mobile App Users With Visualization of Health Checkup Data and Educational Videos on Lifestyle-Related Diseases: Methodological Framework for Content Development.

JMIR Mhealth Uhealth 2020 10 21;8(10):e20982. Epub 2020 Oct 21.

Precision Health, Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.

Background: The number of people with lifestyle-related diseases continues to increase worldwide. Improving lifestyle behavior with health literacy may be the key to address lifestyle-related diseases. The delivery of educational videos using mobile health (mHealth) services can replace the conventional way of educating individuals, and visualization can replace the provision of health checkup data.

Objective: This paper aimed to describe the development of educational content for MIRAMED, a mobile app aimed at improving users' lifestyle behaviors and health literacy for lifestyle-related diseases.

Methods: All videos were based on a single unified framework to provide users with a consistent flow of information. The framework was later turned into a storyboard. The final video contents were created based on this storyboard and further discussions with leading experts and specialist physicians on effective communication with app users about lifestyle-related diseases.

Results: The app uses visualization of personal health checkup data and educational videos on lifestyle-related diseases based on the current health guidelines, scientific evidence, and expert opinions of leading specialist physicians in the respective fields. A total of 8 videos were created for specific lifestyle-related diseases affecting 8 organs: (1) brain-cerebrovascular disorder, (2) eyes-diabetic retinopathy, (3) lungs-chronic obstructive pulmonary disease, (4) heart-ischemic heart disease, (5) liver-fatty liver, (6) kidneys-chronic kidney disease (diabetic kidney disease), (7) blood vessels-peripheral arterial disease, and (8) nerves-diabetic neuropathy.

Conclusions: Providing enhanced mHealth education using novel digital technologies to visualize conventional health checkup data and lifestyle-related diseases is an innovative strategy. Future studies to evaluate the efficacy of the developed content are planned.
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http://dx.doi.org/10.2196/20982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641773PMC
October 2020

Association between tear and blood glucose concentrations: Random intercept model adjusted with confounders in tear samples negative for occult blood.

J Diabetes Investig 2021 Feb 30;12(2):266-276. Epub 2020 Aug 30.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Aims/introduction: To prevent diabetic complications, strict glucose control and frequent monitoring of blood glucose levels with invasive methods are necessary. We considered the monitoring of tear glucose levels might be a possible method for non-invasive glucose monitoring. To develop tear glucose monitoring for clinical application, we investigated the precise correlation between the blood and tear glucose concentrations.

Materials And Methods: A total of 10 participants and 20 participants with diabetes were admitted, and blood and tear samples were collected. Before statistical analysis, we eliminated tear samples contaminated with blood. We observed the daily blood and tear glucose dynamics, and carried out a random intercept model analysis to examine the association between the blood and tear glucose concentrations.

Results: Tear occult blood tests showed that the tear glucose concentrations and their variation increased in both participants with and without diabetes as contamination of blood increased. In both participants with and without diabetes, fluctuations of the plasma glucose concentrations were observed depending on the timing of collection of the samples, and the dynamics of the tear glucose concentrations paralleled those of the plasma glucose concentrations. The random intercept model analysis showed a significant association between the plasma and tear glucose concentrations in participants with diabetes (P < 0.001). This association still existed even after adjusting for the glycated hemoglobin levels and the prandial state (P < 0.001).

Conclusions: It is important to eliminate the tear samples contaminated with blood. Tear glucose monitoring might be a reliable and non-invasive substitute method for monitoring the blood glucose concentrations for diabetes patients, irrespective of glycated hemoglobin levels and timing of sample collection.
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http://dx.doi.org/10.1111/jdi.13344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858102PMC
February 2021

Immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma: Relationship with histopathological and molecular classifications.

Hepatol Res 2021 Jan 15;51(1):5-18. Epub 2020 Jul 15.

Department of Pathology, Keio University School of Medicine.

Tumor tissue is composed of tumor cells and tumor stroma. Tumor stroma contains various immune cells and non-immune stromal cells, forming a complex tumor microenvironment which plays pivotal roles in regulating tumor growth. Recent successes in immunotherapies against tumors, including immune checkpoint inhibitors, have further raised interests in the immune microenvironment of liver carcinoma. The immune microenvironment of tumors is formed because of interactions among tumor cells, immune cells and non-immune stromal cells, including fibroblasts and endothelial cells. Different patterns of immune microenvironment are observed among different tumor subtypes, and their clinicopathological significance and intertumor/intratumor heterogeneity are being intensively studied. Here, we review the immune microenvironment of hepatocellular carcinoma, intrahepatic cholangiocarcinoma and liver metastasis of colorectal adenocarcinoma, focusing on its histopathological appearance, clinicopathological significance, and relationship with histological and molecular classifications. Understanding the comprehensive histopathological picture of a tumor immune microenvironment, in addition to molecular and genetic approaches, will further potentiate the effort for precision medicine in the era of tumor-targeting immunotherapy.
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http://dx.doi.org/10.1111/hepr.13539DOI Listing
January 2021

Telomerase reverse transcriptase (TERT) promoter mutation correlated with intratumoral heterogeneity in hepatocellular carcinoma.

Pathol Int 2020 Sep 19;70(9):624-632. Epub 2020 Jun 19.

Department of Pathology, Keio University School of Medicine, Tokyo, Japan.

Telomerase reverse transcriptase (TERT) promoter mutations are frequently observed in hepatocellular carcinoma (HCC); however, the impact of TERT promoter mutations (TPMs) on clinical features and morphological patterns in HCC remains unresolved. Using DNA extracted from 97 HCCs, correlations between TPM status and both the clinical features of HCC and the immunohistochemically-based subgroups were evaluated. Morphological tumor patterns were semi-quantitatively analyzed using hematoxylin and eosin-stained slides of the whole tumor cross-sectional area. The percentages of tumor area occupied by early, well, moderate and poor histological patterns were calculated as a homogeneity index. TPMs were observed in 53 of 97 (55%) HCCs and were significantly associated with older age (P = 0.018) and HCV-related background (P = 0.048). The biliary/stem cell marker-positive subgroup was less likely to have TPMs (29%) compared to the Wnt/β-catenin signaling marker-positive subgroup (60%). In contrast to TPM-negative HCCs, TPM-positive HCCs clearly exhibited intratumoral morphological heterogeneity (0.800 ± 0.117 vs 0.927 ± 0.096, P < 0.0001), characterized by two or more heterogeneous histological patterns (P < 0.0001) and had more well or early differentiated histological patterns (P = 0.024). Our findings showed that intratumoral heterogeneity was strongly related to TPM-positive HCCs, which established novel roles of TPMs, and may improve our understanding particularly about HCC development and diagnosis.
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http://dx.doi.org/10.1111/pin.12974DOI Listing
September 2020

Insulin- and Lipopolysaccharide-Mediated Signaling in Adipose Tissue Macrophages Regulates Postprandial Glycemia through Akt-mTOR Activation.

Mol Cell 2020 07 27;79(1):43-53.e4. Epub 2020 May 27.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. Electronic address:

The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.
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http://dx.doi.org/10.1016/j.molcel.2020.04.033DOI Listing
July 2020

LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.

Gut 2021 01 6;70(1):180-193. Epub 2020 Apr 6.

Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

Objective: Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic variant in the lysophosphatidylinositol acyltransferase 1 (, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes.

Design: We generated the hepatocyte-specific knockout mice to investigate the function of Lpiat1 in vivo. We also depleted in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids.

Results: The hepatocyte-specific knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride.

Conclusion: We found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.
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http://dx.doi.org/10.1136/gutjnl-2020-320646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788230PMC
January 2021

A case of pancreatic hamartoma with characteristic radiological findings: radiological-pathological correlation.

Abdom Radiol (NY) 2020 07;45(7):2244-2248

Department of Radiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Pancreatic hamartoma is a rare benign tumor. Its preoperative diagnosis is challenging. We present a case of pancreatic hamartoma whose radiological-pathological correlation was evaluated in detail. A 53-year-old man was referred to our institution for diagnosis and treatment. Contrast-enhanced computed tomography (CT) and magnetic resonance image revealed a 3.5 cm long tumor arising from the head of the pancreas with cystic and solid components, the latter of which was gradually and inhomogeneously enhanced in the delayed phase. Fluorodeoxyglucose (FDG) positron emission tomography/CT revealed slight FDG uptake in the solid component. Histologically, a number of pancreatic lobule-like structures, which were mainly composed of aggregates of small ducts embedded in concentric fibrous stroma with no apparent islets or peripheral nerves, were observed in the solid component, whereas multiple dilated ducts were seen in the cystic region. The solid component also contained a narrow area of edematous fibrous stroma with low vessel density, which corresponded with the unenhanced part in the inhomogeneously enhanced solid component. There was no remarkable cytological atypia throughout the mass. A pathological diagnosis of pancreatic hamartoma was made. The radiological findings agree well with the pathological findings. When a pancreatic tumor is of the solid type, preoperatively diagnosing it as pancreatic hamartoma is not possible. However, when a pancreatic tumor with cystic and solid components is inhomogeneously enhanced in contrast-enhanced studies, a diagnosis of pancreatic hamartoma can be considered.
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http://dx.doi.org/10.1007/s00261-020-02425-6DOI Listing
July 2020

An integrated analysis of public genomic data unveils a possible functional mechanism of psoriasis risk via a long-range ERRFI1 enhancer.

BMC Med Genomics 2020 01 22;13(1). Epub 2020 Jan 22.

Division of Bioinformatics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.

Background: Psoriasis is a chronic inflammatory skin disease, for which genome-wide association studies (GWAS) have identified many genetic variants as risk markers. However, the details of underlying molecular mechanisms, especially which variants are functional, are poorly understood.

Methods: We utilized a computational approach to survey psoriasis-associated functional variants that might affect protein functions or gene expression levels. We developed a pipeline by integrating publicly available datasets provided by GWAS Catalog, FANTOM5, GTEx, SNP2TFBS, and DeepBlue. To identify functional variants on exons or splice sites, we used a web-based annotation tool in the Ensembl database. To search for noncoding functional variants within promoters or enhancers, we used eQTL data calculated by GTEx. The data of variants lying on transcription factor binding sites provided by SNP2TFBS were used to predict detailed functions of the variants.

Results: We discovered 22 functional variant candidates, of which 8 were in noncoding regions. We focused on the enhancer variant rs72635708 (T > C) in the 1p36.23 region; this variant is within the enhancer region of the ERRFI1 gene, which regulates lipid metabolism in the liver and skin morphogenesis via EGF signaling. Further analysis showed that the ERRFI1 promoter spatially contacts with the enhancer, despite the 170 kb distance between them. We found that this variant lies on the AP-1 complex binding motif and may modulate binding levels.

Conclusions: The minor allele rs72635708 (rs72635708-C) might affect the ERRFI1 promoter activity, which results in unstable expression of ERRFI1, enhancing the risk of psoriasis via disruption of lipid metabolism and skin cell proliferation. Our study represents a successful example of predicting molecular pathogenesis by integration and reanalysis of public data.
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http://dx.doi.org/10.1186/s12920-020-0662-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977261PMC
January 2020

Clinicopathological features of hepatocellular carcinoma with fatty change: Tumors with macrovesicular steatosis have better prognosis and aberrant expression patterns of perilipin and adipophilin.

Pathol Int 2020 Apr 12;70(4):199-209. Epub 2020 Jan 12.

Department of Pathology, Keio University School of Medicine, Tokyo, Japan.

The clinicopathological characteristics of steatosis in hepatocellular carcinoma (HCC) remain unclear. Here, we elucidate the features of macrovesicular steatosis (MaS) and microvesicular steatosis (MiS) in HCC and their relationships with background liver steatosis. A total of 165 HCC lesions were classified as MaS-HCC, MiS-HCC, or conventional HCC (cHCC) according to the cutoff value of 30% MaS or MiS in tumor cells. We analyzed the clinicopathological differences among these groups. MaS-HCC had less portal vein invasion, a higher proportion of HCC with intratumoral fibrosis, and a lower cumulative risk of recurrence than MiS-HCC or cHCC. Moreover, both MaS-HCC and MiS-HCC had lower incidences of hepatitis virus infection and higher levels of HbA1c than cHCC. Background liver steatosis was also higher in MaS-HCC than in cHCC. Immunohistochemical expression of perilipin (Plin1) and adipophilin (ADRP), major proteins expressed on lipid droplet membranes, revealed that almost all lipid droplets in HCC were Plin1 negative, whereas those in background liver were positive. In contrast, ADRP was expressed on lipid droplets in both HCC and background liver. We concluded that MaS-HCC and MiS-HCC were associated with metabolic abnormalities but exhibited different biologic behaviors. Furthermore, lipid droplets in HCC were pathophysiologically different from those in background liver.
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http://dx.doi.org/10.1111/pin.12889DOI Listing
April 2020

Late-Evening Carbohydrate and Branched-Chain Amino Acid Snacks Improve the Nutritional Status of Patients Undergoing Hepatectomy Based on Bioelectrical Impedance Analysis of Body Composition.

Gastrointest Tumors 2019 Oct 29;6(3-4):81-91. Epub 2019 Aug 29.

Hepato-Biliary-Pancreatic Surgery Division and Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: This prospective study measured body composition based on bioelectrical impedance analysis (BIA) in relation to preoperative and postoperative nutritional support and status in patients undergoing liver surgery.

Methods: Thirty-seven patients with impaired liver function (indocyanine green retention rate at 15 min >15%) undergoing hepatectomy for hepatocellular carcinoma or colorectal liver metastasis were enrolled. The control group ( = 10) received no nutritional supplementation. The late-evening snack (LES, = 26) group received a 210-kcal snack comprising a carbohydrate with branched-chain amino acids for 2 weeks before surgery through to 12 weeks after surgery. BIA of body composition, including body cell mass and skeletal muscle volume, was performed.

Results: Although there was no sarcopenia based on the consensus report of the Asian Working Group 2 weeks before surgery, the skeletal muscle volumes in the control and LES groups were at the lower limit of the normal range. Body cell mass and skeletal muscle volume were significantly lower in the control group than in the LES group at 4 ( = 0.03) and 12 ( = 0.02) weeks after surgery.

Conclusion: Late-evening carbohydrate and branched-chain amino acid snack supplementation may improve nutritional status in patients with impaired liver function undergoing hepatectomy.
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http://dx.doi.org/10.1159/000501452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873063PMC
October 2019

Innate Lymphoid Cells in the Induction of Obesity.

Cell Rep 2019 07;28(1):202-217.e7

Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan; Deparment of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan. Electronic address:

Complex interactions between immune cells are an important component in the induction of obesity. Here, we show that Il2rgRag2 mice lacking all lymphocytes are resistant to diet-induced obesity. Transplantation of bone marrow cells from Rag2 mice, which lack only acquired immune cells, into Il2rgRag2 mice abolishes this resistance, indicating a role for innate lymphoid cells (ILCs) in this process. Mice lacking ILC2 or ILC3 cells, but not natural killer cells, are resistant to obesity. Adoptive transfer of naive ILC2s isolated from the small intestine (SI), but not ILC2s from white adipose tissue (WAT), restores the induction of diet-induced obesity in Il2rgRag2 mice. Analysis of transcriptional differences reveals that SI-ILC2s express higher levels of IL-2 than do WAT-ILC2s and that blockade of IL-2 signaling impairs weight gain and reduces the populations of ILC2s and ILC3s in the SI, suggesting a role for the IL-2/ILC2/3 axis in the induction of obesity.
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http://dx.doi.org/10.1016/j.celrep.2019.06.016DOI Listing
July 2019

Differential effects of diet- and genetically-induced brain insulin resistance on amyloid pathology in a mouse model of Alzheimer's disease.

Mol Neurodegener 2019 04 12;14(1):15. Epub 2019 Apr 12.

Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: Based on epidemiological and experimental studies, type 2 diabetes mellitus (T2DM), especially insulin resistance that comprises the core mechanism of T2DM, has been recognized as a significant risk factor for Alzheimer's disease (AD). Studies in humans and diabetic AD model mice have indicated a correlation between insulin resistance and increased amyloid deposition in the brain. Paradoxically, mice with targeted disruption of genes involved in the insulin signaling pathway showed protective effects against the AD-related pathology. These conflicting observations raise an issue as to the relationship between dysregulation of insulin signaling and AD pathophysiology.

Methods: To study the causal relations and molecular mechanisms underlying insulin resistance-induced exacerbation of amyloid pathology, we investigated the chronological changes in the development of insulin resistance and amyloid pathology in two independent insulin-resistant AD mouse models, i.e., long-term high-fat diet (HFD) feeding and genetic disruption of Irs2, in combination with dietary interventions. In addition to biochemical and histopathological analyses, we examined the in vivo dynamics of brain amyloid-β (Aβ) and insulin by microdialysis technique.

Results: HFD-fed diabetic AD model mice displayed a reduced brain response to peripheral insulin stimulation and a decreased brain to plasma ratio of insulin during the hyperinsulinemic clamp. Diet-induced defective insulin action in the brain was accompanied by a decreased clearance of the extracellular Aβ in vivo and an exacerbation of brain amyloid pathology. These noxious effects of the HFD both on insulin sensitivity and on Aβ deposition in brains were reversibly attenuated by dietary interventions. Importantly, HFD feeding accelerated Aβ deposition also in the brains of IRS-2-deficient AD mice.

Conclusions: Our results suggested a causal and reversible association of brain Aβ metabolism and amyloid pathology by diet-dependent, but not genetically-induced, insulin-resistance. These observations raise the possibility that the causal factors of insulin resistance, e.g., metabolic stress or inflammation induced by HFD feeding, but not impaired insulin signaling per se, might be directly involved in the acceleration of amyloid pathology in the brain.
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http://dx.doi.org/10.1186/s13024-019-0315-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460655PMC
April 2019
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